In genetic disease, abnormalities occur in genes for various reasons and can interfere with life activities. Abnormalities among them due to nonsense mutations, because the stop codon occurs in the middle of a structural gene, suppress expression of a full-length protein having a function, triggering various genetic diseases. There are said to be 2500 or more nonsense mutation-type genetic diseases. Replacement therapy is exceptionally successful in hormone deficiency due to genetic abnormality, but there generally is not yet any direct method of treating genetic diseases. We currently rely on symptomatic treatment to alleviate symptoms, and no treatment leading to a complete cure has been discovered. Gene therapy is one of the most promising treatments, but this treatment has not reached a stage that can withstand clinical application.
Duchenne muscular dystrophy seen in male children can be given as an example of a typical genetic disease. In this disease, a mutation occurs on the dystrophin gene present in the X chromosome. A stop codon is formed by this mutation (premature stop codon), and expression of normal dystrophin and dystrophin-associated proteins is inhibited by the interruption and cessation of translation at this mutation site. As a result, dystrophin proteins are lacking, and muscular dystrophy occurs.
The use of compounds having read-through activity to treat nonsense mutation-type diseases has been reported. When a specific compound is administered to a patient having a premature stop codon due to a nonsense mutation and lacking a specific protein, a phenomenon is seen whereby the compound acts on the ribosomes and the ribosomes read through and translate the stop codon. This phenomenon is called read-through. As a result of read-through, a wild-type normal protein is synthesized, and the disease can be treated. Gentamicin, which is an aminoglycoside antibiotic, is known as a compound having such read-through activity. When gentamicin is administered to a Duchenne muscular dystrophy patient, dystrophin proteins are reported to accumulate (see Non-patent Reference 1). It is also reported that the typical electrophysiological abnormalities can be normalized by administering locally to the airway epithelium of a cystic fibrosis patient (see Non-patent Reference 2). However, gentamicin, like other aminoglycoside antibiotics, has severe renal toxicity and ototoxicity and is unsuited to this treatment method which will likely require long-term administration. It is also necessary to separate the drug effect from the antimicrobial activity that this compound has in consideration of adverse effects and the like.
Negamycin (methylhydrazinoacetic acid-linked δ-hydroxy-β-lysine: NM), a dipeptide antibiotic, is also reported to have read-through activity. When negamycin is administered to muscular dystrophy model mice, the expression of dystrophin is reported to recover (see Patent Reference 1). However, since negamycin also has high antimicrobial activity, it is desirable in consideration of adverse effects to provide a therapeutic drug for nonsense mutation-type diseases having selective read-through activity.